Myocardial ischemia, infarction, and heart failure constitute a disease spectrum which is rapidly becoming one of the foremost global health challenges. Current therapies focus upon pharmacologic optimization and macrorevascularization via PCI and CABG. Reconstructive and replacement therapies are limited in applicability or availability. A significant unmet need is that of microrevascularizatio. Repeated studies have demonstrated survival advantage in patients with robust collateralization. Thus the presence of endogenous revascularization and repair mechanisms exist and the benefits are clear; but the native potency is generally inadequate. In the initial funding period, we studied the primary effectors of endogenous microrevascularization, endothelial progenitor stem cells (EPC) and their potent chemokine stromal cell derived factor 1-alpha (SDF). We were able to significantly augment microvascular angiogenesis and improve local tissue biomechanical properties, ventricular geometry and cardiac function after myocardial ischemic injury. Via computational protein engineering, we then designed and synthesized a supra-efficient SDF analog as well as initiated a project to embed EPCs in a vitronectin-based extracellular-matrix simulating scaffold to enhance cell retention and survival. Elements of this work have been upscaled into a preclinical sheep model and also translated into a recently initiated human clinical trial at our institution. In this renewal application we propose to study in further depth the specific interactive mechanisms underlying SDF-mediated EPC neovasculogenesis, develop novel, clinically translatable delivery platforms that enhance EPC function and survival, and refine these in our preclinical sheep model in preparation for potential human clinical investigation. Specific Aim 1 will focus on elucidating mechanistic insights via eGFP marrow reconstitution and tracking, a novel myocardial-specific SDF conditional knockout mouse, and optical fluorescence quantification of cellular level perfusion, oxygenation and energetics. Specific Aim 2 will develop innovative cellular composites based upon biologic extracellular matrix, cell sheet technology and synthetic 3-dimensional printed microscaffolds. Specific Aim 3 will transition this therapeutic strategy into a preclinical sheep model in minimally invasive operative and catheter- based approaches. We have generated the preliminary scientific components and assembled the team expertise to hopefully successfully achieve these goals.